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A Nobel victory

Distinguished Professor of Chemistry and Biochemistry Arieh Warshel’s journey to winning the Nobel Prize has been an intriguing one — from his birth on a kibbutz in Israel to his time at the University of Cambridge, England, where he published his seminal work, to his revolutionary research at USC Dornsife. (Photo/Max Gerber)

It began with an off-the-cuff remark. When enrolling at Technion, the Israel Institute of Technology in Haifa, Arieh Warshel asked his friend Eliezer Finkman what he should study.

“Chemistry, because you have good vision,” replied Finkman, an army buddy of Warshel’s who was a student at Technion.

“He assumed since he wore glasses, and I did not, I had good color vision,” Warshel recalled with a shrug. “He thought chemists should see well.”

Warshel filled out “chemistry” under field of study and thus began a lifelong obsession that culminated in October when Warshel, 72, won the 2013 Nobel Prize for Chemistry, along with Michael Levitt and Martin Karplus.

The groundwork for his achievement dates to when Warshel was a doctoral student in the 1960s at the Weizmann Institute of Science in Israel. There, he started working with Shneior Lifson, who envisioned that molecules and their behavior could be modeled by computers.

Warshel started writing computer programs modeling the structure of medium-sized molecules. In 1967, he joined with Levitt, then a pre-doctoral student, to develop an extremely powerful program that could measure the vibrations of any molecule, including large ones. At the time, the pair’s accomplishment was considered novel and outlandish.

Today, it is the basis of all molecular modeling programs.

“There were experimentalists in Israel who heard I was taking big molecules and using our program to calculate vibrations,” Warshel recalled. “They said that was completely impossible.”

Doing the impossible

The Distinguished Professor of Chemistry and Biochemistry at the USC Dornsife College of Letters, Arts and Sciences told his story in his office packed with books and computers. Manila folders were stacked high on his desk. Photos were tacked on a bulletin board, including a few snapshots of his wife of 47 years, Tamar.

Sitting at a small table, occasionally leaping up to zip across the room and pull out a book or a photo to illustrate his story, Warshel often paused mid-sentence to offer insight on a topic.

To prove the “impossible,” Warshel said he first used a Golem computer built at Weizmann. The name “Golem” was derived from a legendary anthropomorphic being created out of inanimate matter in Middle Ages Prague.

The Golem computer “had the highest accuracy,” Warshel said. “This allowed me to check whether my first derivatives that describe the forces on the atoms — the key to the design of the general program — were correct. Instead of writing the formulas, I just tried to get the forces by seeing how the energy changes while moving atoms from left to right on the computer.

After earning his doctorate in 1969, Warshel conducted postdoctoral research in the laboratory of Karplus at Harvard University. Karplus used quantum mechanics to study very small molecules. Warshel had already experimented with adding a quantum portion to the classical description of a medium-sized molecule. Warshel and Karplus decided to research medium-sized molecules with double bonds by combining the classical description from the Weizmann program with the quantum description of double bonds.

Returning to Weizmann as a senior scientist, Washel was joined by Levitt, who had just earned his PhD. The two continued collaborating and in 1976 published their seminal work while at the University of Cambridge, England. This work combined quantum and classical descriptions of molecules, which allowed them to describe actual chemical bonds breaking down inside enzymes.

It took the world four decades to catch up with the ideas of Warshel, Karplus and Levitt.

“First, people would say that what you are doing is impossible,” Warshel said. “So this goes on for 10 years. Then they would say what you are doing is trivial. And then they would say they invented it first. So there was this process, which took a long time.”

Meanwhile, in his USC Dornsife computation laboratory, Warshel has been using computer models to study how proteins transfer signals within a single cell.

“The experimental community was not so anxious to say that this was figured out by computation,” Warshel said. “And I’m going even farther by saying that you cannot even ask the questions without the computer. And in this respect, suddenly the Nobel Prize makes you [look] like a guru. So now, suddenly, I’m certified as correct.”

Now wearing glasses, Warshel gave his signature subtle smile with just the corners of his mouth turning up. If he appears to know something we all don’t, that is because he does.

“When you’re creative, your ideas often don’t catch on very quickly,” said Chi Mak, professor and chair of chemistry at USC Dornsife. “[Arieh] thinks different. That’s a hallmark of a genius. But sometimes it’s so different, it’s hard to catch on or buy into. That’s why Arieh has always been a fighter. He’s fought extra hard to get his ideas rooted into the community.”

After Warshel’s breakthrough, the sentiment in the field of chemistry slowly began to shift, Mak said. “There is now more credence given to theoretical chemistry.”

He’s an original

Two USC Dornsife professors were instrumental in bringing Warshel to the university in 1976. Gerald Segal, professor of chemistry at USC Dornsife, was one of them. In the 1970s, he gave a talk at Weizmann, where he met Warshel, then an assistant professor.

“He was clearly a capable and interesting character on the horizon,” recalled emeritus professor Segal, who was then chemistry chair and later became USC Dornsife dean. “His work was very unusual. It caught my eye.”

Segal recounted the reaction of Martin Kamen upon meeting Warshel during interviews. Kamen, professor of biological sciences and chemistry at USC Dornsife, had co-discovered radioactive carbon-14, which revolutionized biochemistry.

The other professor involved in Washel’s recruitment was USC Dornsife Distinguished Emeritus Professor Otto Schnepp, who taught at Technion in the 1960s. One of his students was Warshel. The two subsequently published a paper on the vibrations in molecular crystals.

“I recognized he was a very smart guy,” Schnepp said. “He was looking for a permanent position. … He made a good impression on the faculty so we recruited him. The first thing that impressed people was that he’s very bright, and he has a good sense of humor.

“He always shows originality.”

Warshel said that Schnepp, Segal and Philip Stephens, emeritus professor of chemistry who died in 2012, were the main reasons he chose USC Dornsife.

Since arriving in 1976, Warshel has been elected to the National Academy of Sciences and the Royal Society of Chemistry. He has published more than 350 scientific papers. He has also perfected methods used in the development of new drugs. These methods predict the interaction between drugs and their targets, which allows pharmaceutical designs that supersede empirical experimentation.

“I’m a strong believer that understanding enzymes can help to find better treatment for diseases than experimenting in a blind way,” Warshel said, using, as an example, improving chemotherapy to fight cancer. “If you find a molecule that is really effective and is exactly in the right point in the process that leads to rapid cell division and to cancer, it can be used to create much less painful side effects in chemotherapy.”

G.K. Surya Prakash, professor of chemistry and USC Loker Hydrocarbon Research Institute director, stressed that Warshel’s prize-winning research was conducted at USC.

“His science has stood the test of time,” Prakash said.

Considered the “Sherlock Holmes of chemistry,” Warshel continues to study enzymes.

“Like any great detective, Arieh is driven by his curiosity,” USC Dornsife Dean Steve A. Kay said. “His Nobel Prize not only places him among the world’s most elite scholars, but provides a wonderful example of the value of fundamental scientific inquiry.”

A Kibbutznik at heart

Warshel was born Nov. 20, 1940, at Kibbutz Sde-Nahum in northern Israel. Like most kibbutzim, agriculture and factory work were the primary income.

Growing up, Warshel’s major duty after his studies was working in the fishponds and some weekends picking cotton in the fields. He mainly tended to a large pond, catching carp that was later sent to market.

Warshel’s father, Tzvi, was also a kibbutz carp fisherman. Despite having only an elementary education, he became an accountant. Warshel’s mother, Rachel Spreicher, graduated from high school and worked at the kibbutz as a launderer, goat-cheese churner and in the “shaldag” — the canned fish and grapefruit factory. She was also an aide to an elementary school teacher. Tzvi and Rachel met on the kibbutz, married and had four sons, Arieh being the eldest.

Both sides of Warshel’s family originally came from Poland. Tzvi Warshel and Rachel Spreicher emigrated to then-British-ruled Palestine. Most of Tzvi’s immediate family perished in 1941 in Lachowicze, Poland, when the Nazis rounded up all Jewish inhabitants into the marketplace and murdered them. Rachel’s mother and two sisters also perished in the Holocaust.

Warshel was not the first in his family to excel in science. His paternal aunt, Chana, studied engineering at the Technion, the first family member to enroll in college. She was killed in Lachowicze along with her grandfather, grandmother and other family.

Finishing what Chana began, Arieh became the first family member to graduate from college.

A dual citizen of the United States and Israel, Warshel fought in the Israeli Army as communications officer of a tank regiment during the June 1967 Six-Day and October 1973 Yom Kippur wars. He is a reservist. A scar on his right ear is a reminder of his close brush with death when a bullet pierced his helmet.

Photos taken before he joined the army show Warshel with a thick head of dark hair and a cool yet vulnerable expression that earned him the nickname of “a young James Dean.” He met Tamar “Tami” Fabrikant through her cousin, who was Warshel’s classmate at Technion. They wed in 1966 and have two daughters, Merav and Yael.

Those close to Warshel say he brought his fighting spirit and work ethic to his computation lab at USC Dornsife. A few days after his Nobel Prize was announced, he was toiling in his lab with his students.

For Warshel, getting to this point has been a pilgrimage.

“To say this is sweet revenge would be wrong,” Mak said. “For Arieh, this is sweet victory.”